分类: 生物学 >> 生物物理学 >> 免疫学 提交时间: 2016-05-12
摘要: Tumor resistance is a major hurdle to anti-Her2/neu Ab-based cancer therapy. Current strategies to overcome tumor resistance focus on tumor cell-intrinsic resistance. However, the extrinsic mechanisms, especially the tumor microenvironment, also play important roles in modulating the therapeutic response and resistance of the Ab. In this study, we demonstrate that tumor progression is highly associated with TAMs with immune-suppressive M2 phenotypes, and deletion of TAMs markedly enhanced the therapeutic effects of anti-Her2/neu Ab in a HER2/neu-dependent breast cancer cell TUBO model. Tumor local delivery of IL-21 can skew TAM polarization away from the M2 phenotype to a tumor-inhibiting M1 phenotype, which rapidly stimulates T cell responses against tumor and dramatically promotes the therapeutic effect of anti-Her2 Ab. Skewing of TAM polarization by IL-21 relies substantially on direct action of IL-21 on TAMs rather than stimulation of T and NK cells. Thus, our findings identify the abundant TAMs as a major extrinsic barrier for anti-Her2/neu Ab therapy and present a novel approach to combat this extrinsic resistance by tumor local delivery of IL-21 to skew TAM polarization. This study offers a therapeutic strategy to modulate the tumor microenvironment to overcome tumor-extrinsic resistance.
分类: 生物学 >> 生物物理学 >> 肿瘤学 提交时间: 2016-05-12
摘要: The signal transduction pathway initiated by vascular endothelial growth factor-vascular endothelial growth factor receptor 2 (VEGF-VEGFR2) plays an important role in the angiogenesis of tumors. The effective antagonists of VEGFR2 would behave as potent drugs for the treatment of malignant cancers. In our study, specific binding peptides with high affinity to VEGFR2 were obtained through bacterial display technology. Conserved motif (FF/YEXWGVK) among those peptide sequences was discovered. One of the selected peptides, VRBP1 (YDGNSFYEMWGVKPASES) was identified by screening the biased bacterial peptide library and its physiochemical feature was further characterized. The results of surface plasmon resonance (SPR) assay indicated that the dissociation constant (K-D) value of VRBP1 was 228.3 nM and this peptide competed with VEGF binding to VEGFR2. Particles conjugated with VRBP1 could recognize the human umbilical vein endothelial cells (HUVEC) which express VEGFR2 on the surface. Further therapeutic effect of VRBP1 was examined by in vivo experiments. VRBP1 could result in a significant decrease in tumor size of H460 xenografts. The results from the immunohistochemical assay showed that CD31 positive signals in VRBP1-treated group were fewer than those in the control ones. These data highlighted the potential of VEGFR2-binding peptides as effective molecules for cancer diagnosis and therapy.
分类: 生物学 >> 生物物理学 >> 肿瘤学 提交时间: 2016-05-11
摘要: Dasatinib-based therapy is often used as a second-line therapeutic strategy for imatinib-resistance gastrointestinal stromal tumors (GISTs); however, acquired aberrant activation of dasatinib target proteins, such as c-KIT and PDGFR13, attenuates the therapeutic efficiency of dasatinib. Combination therapy which inhibits the activation of dasatinib target proteins may enhance the cytotoxicity of dasatinib in GISTs. Bortezomib, a proteasome inhibitor, significantly inhibited cell viability and promoted apoptosis of dasatinib-treated GIST-TI cells, whereas GIST-TI cells showed little dasatinib cytotoxicity when treated with dasatinib alone, as the upregulation of c-KIT caused by dasatinib itself interfered with the inhibition of c-KIT and PDGFRI3 phosphorylation by dasatinib. Bortezomib induced internalization and degradation of c-KIT by binding c-KIT to Cbl, an E3 ubiquitin-protein ligase, and the subsequent release of Apaf-1, which was originally bound to the c-KIT-Hsp903-Apaf-1 complex, induced primary apoptosis in GISTTI cells. Combined treatment with bortezomib plus dasatinib caused cell cycle arrest in the G1 phase through inactivation of PDGFRP and promoted bortezomib-induced apoptosis in GIST-TI cells. Our data suggest that combination therapy exerts better efficiency for eradicating GIST cells and may be a promising strategy for the future treatment of GISTs. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
分类: 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学 提交时间: 2016-05-05
摘要: Oxidative stress is a major cause of sporadic Parkinson's disease (PD). Here, we demonstrated that c-Abl plays an important role in oxidative stress-induced neuronal cell death. C-Abl, a nonreceptor tyrosine kinase, was activated in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced acute PD model. Conditional knockout of c-Abl in neurons or treatment of mice with STI571, a c-Abl family kinase inhibitor, reduced the loss of dopaminergic neurons and ameliorated the locomotive defects induced by short-term MPTP treatment. By combining the SILAC (stable isotope labeling with amino acids in cell culture) technique with other biochemical methods, we identified p38 alpha as a major substrate of c-Abl both in vitro and in vivo and c-Abl-mediated phosphorylation is critical for the dimerization of p38 alpha. Furthermore, p38 alpha inhibition mitigated the MPTP-induced loss of dopaminergic neurons. Taken together, these data suggested that c-Abl-p38 alpha signaling may represent a therapeutic target for PD.